Heart failure and arrhythmias are among the most significant causes of premature death in the United States. Activation of renin-angiotensin (Angll)-aldosterone (Aldo) signaling (RAAS) is a common feature of structural heart disease that leads to heart failure and is associated with arrhythmias. Drugs that inhibit RAAS are cornerstones for reducing death in heart failure patients, but the specific 'downstream'cellular signals that are activated by RAAS and represent the proximate cause of adverse structural and pro- arrhythmic electrical remodeling in heart failure are incompletely understood. RAAS causes increased oxidant stress and may increase cellular Ca2+. Our group has found that RAAS causes increased activity of the multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII) and that CaMKII inhibition prevents or significantly reduces cardiac hypertrophy during RAAS. CaMKII has recently emerged as a pathological signal in heart failure and arrhythmias, and these findings mark CaMKII as a previously unrecognized but necessary signal for pathological RAAS. We have developed evidence that RAAS can activate CaMKII by cellular Ca2+ mobilization (a conventional mechanism) and by a novel, previously unidentified mechanism involving oxidant modification of susceptible amino acid residues in the CaMKII regulatory domain. NADPH oxidase is an enzyme complex that generates reactive oxygen species (ROS) during RAAS, and our preliminary findings suggest that NADPH oxidase is required for maximal CaMKII activity during RAAS. We will answer key questions posed in response to these preliminary findings using the following Specific Aims: 1. Determine the mechanism for CaMKII activation by Angll 2. Determine the role of Angll signaling through NF-kB and MEF2 3. Determine the role of CaMKII in Aldo signaling. The proposed studies will provide critically needed new knowledge of the mechanistic links between RAAS and important clinical phenotypes of cardiac hypertrophy, dysfunction and arrhythmias.